Quaternary salts of substituted diphenylalkanoic acid amides



United States P 2,823,233 atented Feb. 11, 1958 This invention relatesto a new class of organic compounds of therapeutic value and methods forthe preparation thereof. More particularly, this invention relates toquaternary salts of substituted diphenylalkanoic acid amides.

This application is a continuation-in-part of my prior, copendingapplication, Serial No. 185,162, filed September 15, 1950, and nowabandoned.

Bockmiihl and Ehrhart, German Patent 731,560, disclose several amideswhich are stated to vhave antispasmodic activity. Specter, U. S. Patent2,647,926, also discloses an amide and its acid addition salts stated tohave therapeutic value. There is now discovered, according to thepresent in vention, a new class of compounds of the gener wherein Rrepresents a member selected from the group consisting of hydrogen andmethyl; R, and R each represent a member selected from the groupconsisting of alkyl groups containing one to four carbon atoms and, whentaken together with the nitrogen atom, represent a member selected fromthe group consisting of piperidyl'," morpholinyl, pyrrolidyl andpipecolyl; R represents a member selected from the group consisting ofbenzyl and alkyl containing one to eighteen carbon atoms; and Xrepresents one equivalent of an anion selected from the group consistingof chloride, bromide, iodide, alkyl sulfate and aryl sulfonate in ioniclinkage with the nitrogen atom.

The compounds of the present invention possess their ability to suppressgastric secretion of acid and to dilate the pupil of the eye. v

The compounds of the present invention may be prepared by causing anappropriate basic amide to react'with an alkyl halide, an aralkylhalide, an alkyl sulfate, or an aryl sulfonate. The compound in which Xrepresents chloride may be conveniently prepared by causing thecorresponding iodide to react with silver chloride, filtering off thesilver iodide and recovering the desired quaternary chloride from thefiltrate.

The basicv amides from which the quaternary salts are derived can beprepared conveniently by the general procedure exemplified by thepreparation of alpha, alphadiphenyl-gamma-diethylaminobutyramide, asfollows:

A stirred mixture of 386.5 g. (2 moles) of diphenyl acetonitrile and46.5 g. (2.03 moles) of lithium amide in 750 ml. ,of benzene was slowlybrought to boiling. After refluxing the mixture for two hours a driedsolution of 2.09 moles of beta-diethylaminoethyl chloride (prepared bythe method of Slotta and Behuisch, Ber., 68, 754 (1935)), in 600 ml. ofbenzene was added at a rate to maintain gentle reflux. After boiling themixture overnight (15 hours) enough water was'cautiously added todestroy all excess lithium 'arriide aiid to dissolve allstilid;

material, and the benzene layer "wesextracted with oiie I; 80 i by oneof two methods. Typical examples of each method potassium carbonate, anddistillation yielded 454 g.

(77.5%) of alpha, alpha-diphenyl-gamma-diethylamino: butyronitrile as ayellow oil; B. P. l99203 -C./6 mm. Over a twenty-minute period 212 g.(0.68 mole) of the above nitrile was added to a stirred mixture of340ml. of concentrated sulfuric acid and 34 'ml. of water, thetemperature being kept below 90 C. The stirred mixture was heated fortwo hours on the steam bath, poured onto crushed ice, and neutralizedwith concentrated am-. monium hydroxide. The white precipitate "wasfiltered, washed with water and dissolved in chloroform." This solutionwas washed in turn with 5% sodium hydroxide, water and saturated sodiumchloride solution and was then dried over anhydrous potassium carbonateand the chloroform was removed by distillation. Recrystallization of theresidue from petroleum ether (B. P. 85-100 C.) followed by an additionalrecrystallization from isopropanol gave 190 g. (90.5%) 'of alpha,alpha-diphenyl-gamma-diethylaminobutyramide; M. P. 9192.5 C

Additional information on intermediates and methods of preparation ofthe compounds of the present invention is given in J. Organic Chemistry,vol. 17, pages 770-777 1952 t The basic nitriles useful for hydrolysisto amides from which the quaternary salts are'derivedcan bepi'epared.

are given below followed by tabulation of physical-proptrile.Diphenylacetonitrile (42.5 grams) and lithium amide (5.1 grams)are stirred in refluxing toluene (300 ml.) for three hours. To thismixture is added dropwise a solution of 'y-diethylaminoneopentylchloride in 200 ml. of toluene, which has been prepared by stirring 47.3grams J of 'ydiethylaminoneopentyl chloride hydrochloride withtionmixture is then stirred and refluxed. overnight. After cooling,water is added to dissolve the lithium, chloride therapeutic utility byvirtue of their lack of toxicity andv and the aqueous'layer isdiscarded' The toluene layer is washed twice with dilute hydrochloricacid, the acid extracts basified with alkali and the. basic mixture ex-.tracted several times with ether.

nitrile. METHOD B oz,a-Diphenyl-w-(I-piperidyl) capronitrile.-A mixtureof 212.5 grams of diphenylacetonitrileand 27 .8 grams. of

' lithium amide in 1.7 liters of toluene is heated under reflux and thesolvent evaporated, finally under reduced pressure i to remove anyunreacted 1,4-dichlorobutane.

There remains 200 grams of crudew-chloro-a,a-diphenylcapronitrile as ared oil.

Seventygrams of piperidine and 117.5 grams of crude w-chloroa,u-diphenylcapronitrile are heated together in 250 ml. of refluxingtolueneffor 16 hours. The cooled reaction mixture is washed with water,then extracted The ether extracts are. combined, dried, and distilled.There is obtained.48.2 grams of5.diethylamino-4,4-dimethy1-2,2-diphenylvalero- TABLE L-BASIC NITRILESH: CN

R C Bin-NR! Analyses Yield, B. P., Pres., M. P. or R 0.13: -NR': Mcth.percent C. lll'll m, Formula Carbon Hydrogen Cald. Fnd. Cald. Fnd.

00H: -(CH7)4- NCH o B 206-265 1. 0 81. 5-83. 5 CzaHzsNn CUHB (CH2)5-N(C2H5)n 'B 16 190-197 2. 5 zsHm z 1 CuHs (CH2)0 -N(C21l5)2 B 27197-204 1. O cg HsgNg 82. 7 81. 9 9. 3 9. 1 OH: (CHz)o CsHm B 36 231-2403. O 0251132192 833 83. 0 9. 6 9. 2 QHIS 0112" (CH3)1OH2 N(CH3)2 A 73 1e 139. 0-141..5 oz HzuNz' H01 73. 6 73v 3 7. 9 7. 8 ctHfi-CH2-C(CHa)2-C1I2 N(C2H5)2 A 66 176-176 2. 5 46. 0-50. 0 231130. 2 82. 682. 6 9. 0 9. 2 CtHs -DH2C (CHa)2-GH:- --NCsH1o A 61 183-186 2. 0 66.0-68.11 CraHaoNz 83. 2 83. O 8. 7 8; 9

H -CH7C (C Hs)2-CH7- -NC5H10 A 76 161-165 1. 0 1. 5156 CBHMNQ 80. 6 80.1 9. 7' 9. 8 CH8 2-0112- 'N(CH3)7 A 121-127 2. O 1. 5086 CUHIBNZ- H0165. 4 65. 8 8. U 8. 3 C2115 CH:CH2 -N(C2H5)2 A. 58 126-136 1. 0 1; 4966ClBHM 78. 6 77. 6 9. 9 10. 1 04119 CH3CH2 -N(Cz A 44 149-158 1. 3 1.4976 CrsHzaNz 79. 4 78. 7 10. 4 10. 5 05110 CH2CHg- N (0113M A 69156-162 2. 6 1. 5338 OIEHQJNZI 80. 5 80. 0 9. 6 9. 2

06H CH7CH2 "PUG-11:01 A. 174-177 1. 0 1. 5236 CIBHNN: 79. 9 79. 8 9. 79. 6 051150112 -CH2CH2 C511) A 33 92-11-944) CzzHzaN'r 82. 9 82. 8 8. 28. O P- l oHl CH2-CH1- -NC5H 4J A 32 226. 0-228. 6 CnHzsCiNr H01 67. 267. 6 6. 4 6. 6 a-C5H4N CHzCHz- -N (CH3): A 81 165-168 0. 6 CnHnN: 77. 078.0 7. 2 7. 6 EHtN OH2C "N 2115): A 78 173-180 0. 9 QmHzsN: 77. 8 77. 57. 9 8.0

twice with dilute hydrochloric acid. The aqueous extracts are basifiedwith alkali and the'liberated basic nitrile extracted into chloroform.The extracts are combined, dried, and distilled. There is obtained 86grams of w-( 1- piperidyl a,oa-diphenylcapronitrile.

The following examples will serve to illustrate the invention withoutlimiting. it thereto.

Example 1.-Gamma-carbamyl-gamma, gamma-diphenylprapyl (.diethyl')methylammonium iodide isopropylate To a solution of 10 g.-of.alpha,-alplgdiphenyl-gammadiethylamino-butyramide in 150v ml. of ethanolwas added 10 g. of methyl iodide. In two hours crystals began toseparate. After standing for twenty-four hours, the mixture was cooledin iceand the crystals were collected by filtration. Tworecrystallizations from methanol-isopropanol producedcrystals-meltingat-98-100 C.; yield, 10 g.

Analysis.-Calculated for c rr rN otcnmcHom 55 Calculated Found Example2.(Gamma carbamyl gamma, gamma-diphenylpropyl)trimethylammonium iodide QGONE! 6;.)

C CH:

C/ CH: CH; CH2C 2N m I CH;

' temperature.

Calculated Found Treatment of'thissame base with methyl chloride yieldedsolid, crystalline (gamma-carbamyl-gamma,gammadiphenyl-propyl)-trimethylammonium chloride.

Example 3 .'1-(gamma-carbamyl-gamma,gammadiphenylpropyl)-1-methylpiperidinium iodide CHI-CH3 A mixture of.10 g. ofalpha, alphaediphenyl-gamma-(lpiperidyl) .butyramide, 10 g. .ofmethyl iodide and 200 ml. of isopropanol was allowed to stand for twodays at room The removal of excess methyl iodide and isopropanolbydistillation under diminished pressure left a solid residue which wasrecrystallized from isopropanolmethanol to obtain 8 g..of crystalsmelting at 201-202 C.

Analysis.--Calculated for C H IN O:

Calculated Found 10g. of alpha, alpha-diphenyl ganima-(l-pipridyn--butyramide, 10 g. of methyl bromide and 200 ml. of isopropanolwere mixedat C. in a pressure-tight container, which was then closed and allowedto stand ten days at room temperature. The removal of excess methylbromide and isopropyl alcohol by distillation tinder re= ditced pressurelefta solid residue which was recrystallized from alcohol to givecrystalline l-(gamma-carbamylgamma, 'gamma-diphenylpropyl) lmethylpiperidinium bromide.

Example 4. (Gamma carbamyl gamma, gamma diphenylpropyl) melhylammoniumiodide Five and eight-tenths gram (0.018 mole) of alpha,alphadiphenyl-gamrna-diethylaminobutyramide was dissolved in 50 ml. ofabsolute methanol, g. (0.063 mole) of ethyl iodide was added and themixture was refluxed for 21.5 hours. The solvent was removed underreduced pressure and the residual brown gum wasrecrystallized twice fromabsolute ethanol to a constant M. P. of 182- 183.5 C. (bubbles).

Example 6. 6amma-carliarizyl-gamma cyclohexyl-gamma-phenylpropyl-(dimezhyl ethylammonium iodide Ten and five-tenths grams(0.35 mole) of alpha-cyclohexyl alpha 7 phenyl gammadimethylaminobutyramide and 10.9 g. (0.070 mole) of ethyl iodide weredissolved in 60 ml. of absolute methanol and refluxed for nineteenhours. Removal of the solvent and excess ethyl iodide under diminishedpressure left a brown gum which set up to a yellow solid when cooled andscratched.

fTwo crystallizations from water gave 10.2 g. of white crystals; M. P.187-191 C. (bubbles).

Analysis.Calculatedfor C H IN O:

- Calculated Found Example 7.Gamma-carbamyl-gamma,gamma-diphenylpropyl-(diethyl)methyl-ammonium iodide Analysis.Calculatedfor C H IN O:

Calculated Found Example5.1-(Gamma-carbamyl-gamma-phenylpropyl)-1-methylpiperidinium iodide ICHr-CH:

One-tenth mole (24.6 grams) of gamma-(1-piperidyl)-alpha-phenyl-butyramide was dissolved in 100 ml. ofwarm isopropylalcohol. The solution was cooled to room temperature and 10 ml. ofmethyl iodide added. An exothermic reaction occurred, and soon a heavyoil separated from the solution. The oil gradually solidified, and wascollected by filtration. The crude methiodide amounted to 36.5 grams(94% yield), M. P. 168-180" C. Several recrystallizations from isopropylalcohol containing a little water raised the melting point to 188-190 C.a

The yield of recrystallized material was 27.7 grams.

Analysis.-Calculated for C ll lN o:

Calculated Found 7 0 49. 5 I mi Fl 6. 5 6. 6

Five and two-tenths grams (0.016 mole) of alpha,alphadiphenyl-gamma-diethylaminobutyramide and 5.0 g.

(0.035 mole) of methyl iodide were dissolved in 70 ml.

. of dry isopropanol.

tion was completed by refluxing two hours On cooling 6.4 g. of yellowcrystals of M. P. 164-6 C. (sint. 90 C.) were obtained.Two.recrystallizationsv from acetone gave colorless crystals; M. P.159160 C.

(bubbles).

A nalysis.-Calculated for C H lN o;

7 Calculated Found Example 8.-4-(gamma-carbamyl gamma, gammadiphenylpropyl)-4-ethylm0rph0linium ethyl sulfate CrHaO C\ /CHzC t 6oH.oH.-N o so, C H:- QHaw- (31H: 0

CONH:

C CsHs CHr-CH: Q oHioHr-N o g 76 OSOIOOIHI cm-o i Crystals began toseparate after' an hour of standing at room temperature and the reac,-

Eiye gtams o pha. alphaa inhe y e mma-(t-mo pho- HHYI-lrbULYRfl-Hlidfishydrochloride; was, neutralized. with 50% sodium hydroxide solution andthe base was taken up in chloroform, washed with saturated sodiumchloride solution and dried over anhydrouspptassium' carbonate.

After removal of the solvent 50 m1. of" dry. benzene and 4.6 g. (0.030mole) of diethyl sulfate were added to the white. residuerandg themixture was refluxed for, 16 hours with calcium chloride protection.Deca-ntat-ion of the benzene left a small amount of pinkish gum. It waswashed three times with dry ether and recrystallized from absoluteethanol by addition 015 ethyl acetate to obtain 2.3 g. of well-formedcrystals; M. P. 170-1715 C.

Analysis.-Calculatedfor C H N O S:

A. solution; of*2.0,- g; (0.006 mole-)5 of; alpha-phenyl-alpha-(prchlorophenyl)agamma-piperidyl.butyramide. and 4.0. g; of met-liyliOdldB-lllz 1 50 ml. of" absolute methanol was reflllXfiClf'Ol'" twohours after' standing f'or twenty-four hours atroom temperature.

The solyentwaslrernovedzunder diminished pressure, leavinggaebrownamorphous solid. This. was;diss,ol.vedin water;- but: came; down as a:gumon cooling. When this gum was dissolved in isopropanol and dilutedwith anhydrous ether :1 small amount of a white solid was. obtainedwhich decomposed. over. aawiderange, (1155-130 0.).

Analysis.-Calculated for C H CIIN O:

Calculated Found Calculated Found- Example- 9.I.-(gamma-- carbamylgamma, gamma diphenylpropyl) l-methyI-Z-pipecoliniam-p-toluenesul fomlteCONH; 0H, 00mm on.

C\ (D -Cg: C133, /CEC\: G CHnC rN 011.. caksolocm v CHQCHr-N' on,

g CH; C a O r CH:

A mixture of 1.2 g. of alpha, alpha-diphenyl-gammafipipecolylbutyramide, 3 g of methyl p-toluenesulfonate and ml. of drybenzene was refluxed overnight while protected fromatmosphericnnoisture. After cooling, the solvent was decanted from aviscous oil on the bottom of the flask. The oil wasdissolved in aminimum of absolute alcohol, treated with decolorizing charcoal, andfiltered. Dilution of the filtrate to turbidity with ethyl acetate andsubsequent cooling caused colorless crystals (0.6 g.) to slowly sep ratefrom solution. After desiccation in, vacuo at room temperature, a,sample of the water-soluble saltgave the following, analysis. M. P.170176 C. (dec.)

AnaIysisQCaIcuIatedfor cg n N ossz Example I0.-1 (gamma carbamyl gamma pchlorophenyl gamma phenylpropyl) 1 methylpiperidim'um iodide I QC CH5Cl+ carom-N CHQCHQ CHzGHs CHaI CHr-CH:

CH3 CHPCg Example 1 1.Gamma carbamyl gamma, gamma a'iphenylpropyl(dimethyl)-ethylammonium iodide solidification).

Analysis:-Calculated'for C H IN O:

Calculated Found Treatment of this same base with ethyl chlorideyielded: solid, crystalline (gamma-carbarnyl-gamma, gamma-dinphenylpropyll-(dimethyllethylammonium. hloride.

Example 12.-.-1 (gamma carbamyl gamma phenylpropyl). 1benzylpiperidiniumchloride CONH CHzCl Hz-CH: Q

CONH:

E onions-N c ore-0g. H CHzCHr-N /CH:

o1 cut-cu,

Amixture of 12.3 g. (0.05 mole) of alpha-phenyl-gamma-(1-piperidyl)butyramide, 7.6 g. (0.06 mole) of benzyl chloride and 50ml. of isopropyl alcohol was heated under reflux for four hours.Dilution of the warm reaction mixture with ethyl acetate followed bycooling caused 12.0 g. (64.5% yield) of white solid, M. P. 155162 C., toseparate. Recrystallization from methanol-ether afforded 10.6 g. ofcolorless crystals, M. P. 156.5161 C. which soften at about 150 C. I

Example 13.-I-(gamma-carbamyl-gamma, gamma-diphenylpropyl)-1-ethylpyrr0lidinium ethyl sulfate, hemihydrate a QCHzCHr-N G CHzCHz-N OSOZOCEHB A mixture of 3 g. (0.01 mole) alpha,alpha-diphenylgamma-(1-pyrrolidyl)-butyramide, 30 ml. of dry benzene and3 ml. (3.54 g.) (0.023 mole) of diethyl sulfate was refluxed for fourhours while protected from atmospheric moisture, then cooled and thesolvent was decanted from the viscous light brown oil. The product wasdissolved in hot absolute alcohol, filtered and diluted with ethylCHr-CH:

Cl x-C 2 CON H:

C C2 6 (Illa-C 2 OED-C 2 acetate until turbidity developed. Coolingcaused the,

crystallization of material which was recrystallized from the samesolvent combination to obtain 0.85 g. of product which softened at about105 C. and melted at 130- Analysis.-Calculated for C H N O S- /2H O:

Calculated Example ]4.-1-benzl-I-(gamma-carbamyl-gamma,gamma-diphenylpropyl)-piperidinium bromide monohy- "drate CHgCHI ont@ornm CHrC Q C i cmcHHK cu,- H20 Br cat-0H1 One and one-half grams ofalpha, alpha-diphenyl-gamma- CONH:

(l-piperidyD-butyramide was dissolved in a minimuntml.) of hotacetonitrile, treated with 1 ml. of benzyl bromide (theory 0.56 ml.) andrefluxed for twenty-four hours. Dilution of the cooled mixture with 400ml. of

' dry ether caused 1.7 g. of solid to separate; M. P. 179-181 C.Recrystallization from water after charcoal treatment produced whitemicrocrystals, M. P. 180-181.5 C.; yield 1.2 g.

AnaIysis.-Calculated for C H BrN O-H O:

Calculated Found C 65. 7 66. 1 Fl 6. 88 6. 43

Example 15.--1-(gamma-carbamyl-gamma, gamma-diphenylpropyl.)1-methylpyrr0lidinium iodide CONE CHzCHr-N\ +CHzI 1 CHz-CH: 3

C CH: CHr-CH:

I CHt-CH A mixture of 2 g. of alpha,alpha-diphenyl-gamma-(lpyrrolidyl)-butyramide, 35 ml. of anhydrousisopropyl alcohol and 2 ml. of methyl iodide was protected from moistureand refluxed overnight. Dilution with dry ether to a volume of 250 ml.caused the yellow product to' precipitate. It was dissolved in a minimumof absolute alcohol, treated with decolorizing charcoal, filtered andthe filtrate was diluted with ethyl acetate to a volume of ml. Coolingcaused 2.1 g. of pale yellow crystals, M. P. l0l'-l03 C. to separatefrom solution. After desiccation in vacuo over phosphorous pentoxide, asample gave the following analysis:

Analysis-Calculated for C H IN O:

Calculated Found 7 Example 16.-Gamma-carbamyl-gamma-phenylpropyl methyldiethylammanium iodide Calculated Found Example. 17.Gamma-carbamyl-gammarphenylpropyl. triethylammonium iodide /C\ CsHs HCHa-CHg;N

I CaHs V A solution of 7.1 grams of gamma-carbamyl-gammaphenylpropyldiethylamine and 3.3 ml. of ethyl iodide in 40 ml. of isopropyl alcoholis refluxed for 1.5 hours. Dilution of the reaction mixture with a smallamount of ether induces crystallization of the quaternary. The materialis collected by filtration andrecrystallized from:

a mixture of methyl alcohol and ether to give 7.9 grams of gammacarbamyl gamma phenylpropyl triethylammonium iodide, M. P. l86.5-l87.5C.

Analysis.--Calculated for C16H27ON2I- Calculated Found ExampleI8.Delta-carbamyl-delta, delta-diphenyl-beta, beta-dimethylbutyltrimethylammonium iodide A solution of 6.5 grams ofdelta-carbamyl-delta, deltadiphenyl-beta, beta-dimethylbutyl dimethylamine and'6.2 ml. of methyl iodide in 25 ml. of isopropyl alcohol is.refluxed for two hours. On cooling, a gum separates, which graduallysolidifies.

methyl alcohol and. ether to give 8.2 grams of delta-car-.

bamyl-delta, delta-diphenyl-beta, beta-dimethylbutyl :tri-

methylammonium iodide, M. P. 211.0-2125" C.

Analysis-Calculated for C H ON I:

Calculated Found Example 19. Gamma-carbamyl-gamma,gamma-diphenyl-alpha-methylpropyl 'ethyl dimethylammonium is. evaporatedunder reduced pressure. Recrystallization of the solid, residue frommethyl alcohol gives 6.0 grams of gamma carbamyl gamma,gamma-diphenyl-alphamethylpropyl ethyl dimethylammonium iodide, M.' P.192.0-192.5 C.

Analysis.Calcu1ated for, C H ON I:

Calculated Found The solid material is col lected byfiltration andrecrystallized from a mixture of.

Example 20. Gamma carbamyl .gamma, gamma-all:- phenylpropyl methyldiethylammonium=chloride C CzHa Cl CH3 An excess of "concentratedhydrochloric acid is added to an aqueous solution of 59.4 grams ofsilver nitrate. The precipitated silver chloride is collected byfiltration and Washed successively with several portions of water andthen:m,ethyl alcohol. The silver chloride thus prepared is added to astirred solution of 116.2 grams of gammacarbamyl=gamma,gamma-diphenylpropyl methyhdiethyl: ammonium iodide isopropylatein 400ml. of warm methyl alcohol. The reaction mixture is'refluxedforl6-hoursand then filtered hot to remove the silver iodide.

from amixture of isopropyl alcohol and ether. Severalrecrystallizationsafford 57.0- grams of .gamma-carbamyl gamma, gamma-diphenylpropylmethyldiethylammonium' chloride, M. P. 2l7.52l8.5 C.

Analysis.-Calculated for C H ON Cl:

Calculated ,Found Example 21.Gamma-carbamyl-gamma, gamma-di phenylpropyltriethylammonium chloride C\ 01H: CzH: cat-0H Cl C2115 According to theprocedure described in Example 20,, 102.5 grams of gamma-carbamyl-gamma,gamrna-diphenylpropyl triethylammonium iodide is treated with silverchloride. There is obtained 65.2 grams of gammacarbamyl-gamma,gamma-diphenylpropyl triethylammonium chloride dihydrate, M. P.198.5200.0 C. (recrystallized from isopropyl alcohol).

Analysis.Calculated for C H ON CI-ZH O:

Calculated Found The anhydrous material melts at'204.5-206.0 C. (dec-.-)

Analysis.Calculated for C H ON Cl:

, Calculated Fpundh Example 22. Gamma-carbamyl-gamma,gamma-diphenylalpha methylpropyl a'z'methyl-octadecylammoniam bromide.

Q CONH: I H

CH3 CH3 H Bi'L The filtrate isstripped of solventandtheresiduecrystallized 14.8 grams 0.05 mole) of 4-di1nethylamino-22-diphenylvaleramide, 18.4 grams (0.055 mole) of n-octa- 14Analysis.--Calculated for C H IN O:

decyl bromide and 35 ml. of benzyl alcohol were heated together atsteam-bath temperature for 41% hours. The Calculated Found benzylalcohol was removed by distillation under vac- 46.6 4&8 mum, and theresidue was recrystallized from acetonitrile 6.4' as and again fromacetone, raising the melting point of the 1 waxy whlte Sohd to 7 Example25.'-7 Diethylamino-d-ethyl-d pheiiylbilfyr- Example 23.(Delta carbamyl5,3 dimethyl deltaamlde phenylbutyl) methylpiperidinium iodide l-NR5C-NH: 0 on. CH: I I 1 s C 1C 2 1 s)| H CHaO .H..N

CH3 l 'y Diethylamino oz ethyl a phenylbutyromtrile (48.8- grams) isadded in portions to a cooled mixture of 100 A solution of 7.2 grams of4,4-dimethyl-5-(l-piperidyly ml. of concentrated sulfuric acid and 10ml. of water Z- henyIbutyramide and 14.2 grams of methyl iodide in andthe resulting solution heated' on the steam bath for 100 ml. of methanolis refluxed for twenty hours. On three hours. The solution is poured onice and made dilution with ether, the quaternary iodide crystallizes.basic with ammonium hydroxide. The gumwhich sep- The solid is collectedby filtration and recrystallized from arates is extracted intochloroform and extracts dried methanol-ether; there is obtained 6.1grams of (deltaand the solvents evaporated. The amide, y-diethylaminocarbamyl 5,5 dimethyl deltaphenylbutyl)methyla-ethyl-u-phenylbutyramide, is obtained as a yellowoil v piperidinium iodide, M. P. 2l9.0220.0 C. (43.9 grams).

Analysis.Calculated for C H IN O: Analysis.Calculated for C H N OiCalculated Fmmd Calculated Found 0 53.0 53.1 A H i313 i333 10.7 11.1

Example 24.--'y-Dimethylamino-amethyl-a-phenylbutyrr amide 35y-Carbamyl-y-phenylamyl') diethyl methylammoniumt iodide II CNH: 0.. QCfia CH1--CH2N(CH3)2 40 V Thirty-five grams of'y-dimethylamino-m-methyl-a-phenyl- C61: CHr-CHr-l KCIH'mbutyronitrileis added to a cooled mixture of 70 ml. of concentrated sulfuric acid and7 ml. of water and the resulting clear solution heated on the steam bathf0r 5 A solution of 2 grams of ,TdiethYlamihowCthYLw thireehourssolutlqn 1S Poured 9 'i baslfied phenyl-butyramide and 15 ml. ofmethyl iodide in ml. Wlth m l hydroxldc' The mlxture extracted ofisopropanol is heated to boiling, then diluted slightly sever? tlmeiwlthchloroform; the chloroform extracts. with ethyl acetate. Crystallizationproceeds rapidly. The comlamed l and the solvent evaporaled' T r6517solid is collected by filtration, and recrystallized from recrystallizedfrom cyclohqane to glve P 50 ethanol-ethyl acetate. There is obtained16.4 grams of ammo-ix-methyl-a-phenylbutyramide, M. P. 95.0-96.5 C.(,rcarbamyl 7 phenylamyndiethyl methylammbnium Analyszs.Calculated forCHI-120N201 iodide, M. P. 9 5 72 0o (a Ana ysis-Calculated for C H INO-H O': Calculated Found C 70,9 71.1 gfi fi el i lm Fl 9.2 9.2 N 7 5 c 42 H- 7.4 7.3 ('y-Carbamyl-y-phenylbutyl)trimethylammonium iodide O('y-Carbamyl-v-phenylamyl) triethylammonium iodide V v C-NH: on,CHz-CHz-N(CH3)3I Ten milliliters of methyl iodide is added all at onceto .a 01%: CH:CH:N(C:Hs)aI solution of 8.8 grams of'y-dimethylamino-ot-methyl-uv Pheflylbulylafnide in 80 Of p p A11 Asolution of 14.2 grams of 'y-diethylamino a-ethyl-a thermic reactionsets in and is followed by precipitation phenylbutyramide nd 15 1, ofethyl iodide in 50 mL. of the quaternary iodide. The solid is collectedby filf isopropanol is r fluxed f r five hours, On cooling, tration andrecrystallized from a mixture of methyl and the quaternary iodidecrystallizes. The solid is collected isopropyl alcohols to give 9.3grams of -carbamyl-vby filtration and recrystallized from methanol-ethylacphenylbutyl)trimethylammoniurn iodide, M. P. 243.5- etate to give 10.5grams of 'y-carbamyl-y-phenylamyl'= 245.5 C. ethylammonium iodide, M. P.190.5-192.5 C.

. V v 7 16 Analysis.Calculated for C H IN O: Analysis.-Calculated for CH ClN O:

Calculated Found Calculated Found 51.7 51.9 5 o. 70.3 70.0 H 7.5 7.6 H7.6 8.3 N 6.7 6.4

V V Exa l 29. -Dim rh la inohen l- -2- rid 1- Example26.Isopropyldimethyl ('y-Zarbamyl-7,'y-dim e Z g Z y a py yphenylpropyl) ammonium iodide 0 C CH(C z)a 1'5 CHa-CHr-NwHah I Qcrn-our-l rwrm,

A solution of 42.3 grams of -dimethylamino-a,u-diphenylbutyramide and37.4 grams of isopropyl iodide in 80 ml. of absolute ethanol is refluxedfor 40 hours. The solvent is removed by evaporation under reducedpressure and the residue recrystallized from ethanolethyl acetate. Thereis obtained 35.1 grams of isopropyldimethyl (rycarbamyl-'y,'y-diphenylpropyl) ammonium iodide, M. P. 193.0-l94.0 C.

Analysis-Calculated for C H IN O:

Calculated Found Example 27.Ethyl dimethyl ('y-carbamy'wy-diphenylpropyl) ammonium bromide a 1 A solution of 27.2 grams of'y-dimethylamino-u,a-diphenylbutyramide and 19.8 grams of ethyl bromidein 40 ml. of methanol is refluxed for 64 hours. The solvent is distilledunder reduced pressure and the residual oil triturated with ether. Thesolid quaternary bromide is collected by filtration and may berecrystallized from isopropanol to give ethyldimethyl -carbamyl-,'y-diphenylpropyl) ammonium bromide, M. P. 212.()213.0 C.

Analysis.-Calculated forC H BrN oz 7 Calculated Found Example 28'.Alyldimezhyl ('y carbamyl-yjy dipheiiyl propyl) ammonium chloride i Q0...... 0 OH CH CH 2- Cy Eighty-four grams of'y-dimethylaminO-a-phenyI-a-Z-pyridylbutyronitrile is heated on thesteam bath for three hours with 300 ml. of concentrated sulfuric acidand 30 ml. of water. The solution is poured on ice and basified withammonium hydroxide. The basic mixture is extracted three times withether; the extracts combined, dried, and the'solvent evaporated. ThereWas obtained 68 grams of 'y-dimethylarnino-a-phenyI--Z-pyridyIbutyramide as a thick gum.

Trimethyl ('y-cdrbamyl-y-phenyl-y-Z-pyridylpropyl) ammonium iodide i Q 7auteur-Morton Five milliliters of methyl iodide is added to a Warmsolution of 10 grams of 'y-dimethylamino-u-phenyI-a-Z-pyridylbutyramidein 60 ml. of isopropanol containing one milliliter of water. Seeding andscratching'induces crystallization of the quaternary iodide. The solidis collected by filtration and recrystallized from dilute isopropanol,

giving 12.2 grams of trimethyl(y-carbamyl-'y-phenyl-2-pyr'idylpropyl)ammonium iodide, M. P. 178 C. dec.

Analysis.-Calculated for C H IN O:

Calculated Found Example 30 .--'y Diethylamino a phenyl a 2-pyridylbutyramide CHz-CHa-NKME):

Ninety grams of -diethylamino-or-phenyl-a-2-pyridylbuty'r'onitr'ile isdissolved in a mixture of 300 ml. of concentrated sulfuric acid and 30ml. of Water and the resulting solution heated on the steam bath forthree hours. The solution is poured on ice and made basic with ammoniumhydroxide. The basic amide is removed by several extractions with ether.The extracts are combined,

dried, and evaporated to dryness; the residue solidifies. Onrecrystallizationf rom petroleum ether there is obtained 64 grams ofy-diethylaminowuphenyl-a-2-pyridylbutyramide, M. P. 6367 C.

Analysis-Calculated for C H N O:

Calculated Found Diethylmethyl ('y carbamyl 'y phenyl 7 2 pyridylpropyl)ammonium iodide CHI C-NH:

Hr-C r-Nzfiih V A solution of 10 grams of y-diethylamino-az-pheny1-ot-2-pyridylbutyramide and 11.4 grams of methyl iodide in 60 ml. ofisopropanol containing one milliliter of water is allowed to standovernight at room temperature. Dilution with 200 ml. of ether causesseparation of an oil. The liquid is decanted and the oil dissolved inhot dilute isopropanol. Cooling causes crystallization of the quaternaryiodide. The solid is collected by filtration and recrystallized fromdilute isopropanol, giving 13.2 grams of diethylmethyl ('y carbamyl 'yphenyl 'y 2 pyridylpropyl) ammonium iodide, M. P. 158 C. dec.

Analysis.-Calculated for C H lN o:

Calculated Found A solution of 36.6 grams of diethylamine in benzene isadded to a benzene solution of 50.0 grams of diphenylacetyl chloride andthe resulting mixture refluxed for three hours. The reaction mixture isextracted with water and the benzene layer evaporated to dryness.Recrystallization of the residue gives 48 grams ofN,N-diethyldiphenylacetamide, M. P. 67.5-69.0 C.

A solution of 38 grams of the N,N-diethyldiphenylacetamide in 160 ml. ofxylene is refluxed for five hours with 3.4 grams or lithium amide. Tothis mixture is then added dropwise a solution of 29.5 grams offi-piperidylethyl chloride in 100 ml. of xylene. The reaction mixture isrefluxed overnight, cooled, and poured into water. The xylene layer isseparated and extracted twice with dilute hydrochloric acid. The acidextracts are neutralized with alkali. An oil separates, whichsolidifies. Recrystallization of the solid from petroleum ether gives25.8 grams of N,N diethyl :,0: diphenyl 'y (1 piperidyl)butyramide, M.P. 106.0107.0 C.

Analysis.--Calculated for C H N O:

This base is quaternized, e. g. with alkyl halides such as methyl iodideand ethyl bromide, in the manner of the above examples.

II CAHB C-NH:

. {3 carom-Moira).

Thirty-five grams of a butyl 'y diethylamino .-'a phenylbutyronitrile isadded to a cooled solution of 65: ml. of

18 concentrated sulfuric acid and 6.5 ml. of water. Thereaction mixtureis heated on the steam bath for 3.5 hours, then poured on ice andbasified with ammonium hydroxide. The liberated basic amide is extractedinto ether, the ether extracts combined and dried. Evaporation of thesolvent leaves a. butyl "y diethylamino a phenylbutyramide as viscousyellow oil (22.7 grams).

Analysis.--Calculated for C H N O:

Calculated Found The base is quaternized in the manner described above.

Example 33.-a A cyclohexenyl 'y dimethylaminoa phenylbutyramideCalculated Found The base is quaternized in the manner described above.

Example 34 .Benzyl ('y-carbamyl-'y,'y-diphenylpr0pyl) dimethylammoniumchloride Q CONE.

Calculated Found C 73. 5 7a. 2 H 7. 15 7. 49

Example 35. y-Diisopropylamin0-a,a-diphenylbutyramide'y-Diisopropylamino-a,a-diphenylbutyronitrile (60 g.) was added inseveral portions to a mixture of sulfuric acid ml.)- andwater (15 ml.)and the solution was heated 3% hours on the steam bath and then pouredon ice and made basic. with? NH OH. 'The 'y-diisopropylamino-a,a-

19 diphenylbutyramide precipitated as a solid, which was taken up inmethylene chloride from an aqueous slurry. The methylene chloride wasseparated and dried by filtering through anhydrous K CO The solvent wasremoved by distillation, leaving the amide which was crystallized fromSkellysolve B five times and found then to have M. P. 87.088.5 C.

Analysis.Calculated for C H N O:

Calculated Found 'y-Diisopropylamino-a,a-diphenyl-butyramide methiodideCalculated Found Example 36.'yDi-isopropylamino-a,a-diphenylvaleronitrile and'y-di-isopropylamino-a,adiphenyl-,8-methylbutyranitrilel-di-isopropylamino-2-chloropropane hydrochloride (71.8 g.; 0.336 mole)was stirred with 100 ml. toluene and 45 ml. of 40% sodium hydroxide;after the salt had been completely decomposed, the toluene layer wasdecanted and the aqueous layer was stirred in turn with three 50 ml.portions of toluene. The combined toluene solution was dried by shakingover anhydrous K CO for three hours; this solution was filtered andadded dropwise over one hour to a hot, stirred mixture prepared bystirring diphenylacetonitrile (77.3 g.; 0.4 mole) and lithium amide (9.2g.; 0.4 mole) in 250 ml. refluxing toluene for three hours. The mixturewas stirred and refluxed for 24 hours and water was added to dissolvethe lithium chloride. The aqueous layer was discarded and the toluenelayer was shaken twice with dilute hydrochloric acid. The acid extractswere separated; made basic with sodium hydroxide and the basic materialwhich separated was extracted into ether. The combined ether extractswere shaken with saturated salt solution, and the ether filtered throughanhydrous K CO and the solvent evaporated to leave an oil which wasdistilled at 159-l84 C. (mainly about 184) at 0.4 mm., giving 84.1 g.

The oil was taken up in 200 ml. hot Skellysolve B, allowed to stand inthe cold, and filtered, the filtrate being set aside.

The precipitate of 'y-di-isopropylamino-a,-diphenyl- 7 2i) valeronitrilecollected by this filtration was recrystallized four times fromSkellysolve B, M. P. 97.0100.0 C.

Analysis.-Calculated for C H N Calculated Found Calculated Found Theoriginal Skellysolve mother liquor set aside above, after removal of asecond crop of crystals after further standing in the cold, wasevaporated under reduced pressure to give'y-di-isopropylamino-a,u-diphenyl-fl-methylbutyronitrile as an oil. Tengrams of this oil was used in Example 37 below. The rest of the oil wastaken up in about ml. Skellysolve A, cooled to 50 C. and the 'y diisopropylamino a,a-diphenyl-fi-methylbutyro nitrile which precipitatedwas collected by filtration and found to melt at about 93.5 -97.5 C.after recrystallization from isopropyl alcohol.

Example 37'.-'y-Diis0pr0pylamin0-a, x-diphenyl-fl-methylbutyramide 'yDiisopropylamino up: diphenyl 13 methylbutyronitrile (10 g.) was addedto a mixture of sulfuric acid (25 ml.) and water 2.5 ml. and theresulting solution was heated for 3 /2 hours on the steambath, poured onice and. made basic with NH OH, precipitating the product, 7diisopropylamino a,oz diphenyl B methylbutyramide as a gum, which wasseparated and extracted with methylene chloride. The extracts werefiltered through Na SO and the solvent evaporated to leave the productas an oil which was dissolved in 200 ml. Skellysolve A, filtered andallowedv to stand for two days. The product precipitated as largecrystals, M. P. 114-l18 C. after recrystallizations from aqueousisopropyl alcohol.

Analysis.--Calculated for C H N O:

Calculated Found C 78.36 78.3 H 9.15 9.15 N 7.95 8.00

Example 38.'y-Diisapr0pylamino-a,a-diphenylvaleramide 'yDiisopropylamino ego: diphenylvaleronitrile (18.0 g.) (Example 36 above)was slowly dissolved in a mixture of sulfuric acid (50 ml.) and water (5ml.) and the resulting solution was heated for 3% hours on the steambath, poured on ice and made basic with NH OH, precipitating the product'y-diisopropylaminoa,a-diphenylvaleramide as a white gum. The water wasdecanted and the product dissolved in hot isopropyl alcohol, filtered,and poured into water to precipitate 8.0 g. product, M. P. 192.5l94 C.(softens about C.) after repeated recrystallization from aqueousmethanol and from isopropyl alcohol.

I do not limit myself to the specifically mentioned times, temperatures,quantities, chemicals or steps of procedure, as these are given simplyto clearly describe this invention as set forth in my specifications andclaims, and they may be varied without going beyond the scope of myinvention.

I claim:

1. A compound selected from the group consisting of 'y carbamyldiphenylpropyl trimethylammonium halides, 'y carbamyl 'y,'ydiphenylpropyl dimethylethylammonium halides,-carbamyl-y,'y-cliphenylpropylmethyldiethylammonium halides,-y-carbarnyl-' -diphenylpropyl-triethylammonium halides and'y-carbamyl-y diphenylpropyl-methyldiisopropylammonium halides, saidhalides being selected from the group consisting of chloride, bromideand iodide.

2. 'y Carbamyl 'y,'y diphenylpropyl dimethylethylammonium bromide.

3. 'y-Carbamyl-qw-diphenylpropyl-trimethylammonium iodide.

4. 'y Carbamyl diphenylpropyl methyldiethylammonium chloride.

5. 'y-Carbamy1-'y,'y-dipheny1propyl triethylammonium iodide.

6. 'y Carbamyl 'y,'y diphenylpropyl methyldiisopropylammonium iodide.

References Cited in the file of this patent UNITED STATES PATENTS2,009,144 Miescher July 23, 1935 2,437,545 Martin Mar. 9, 1948 2,647,926Specter Aug. 4, 1953 FOREIGN PATENTS 504,085 Belgium July 14, 19511,054,240 France Oct. 7, 1953 882,283 France May 28, 1943 884,740 FranceAug. 25, 1943 OTHER REFERENCES Cheney et al.: J. Org. Chem, vol. 17, May1952, pp. 770-776.

Hoekstra: J. Pharm. and Exptl. Therap., vol. 98 (1950) p. 14.

Jensen: Acta Chemica Scand., vol. 2, pp. 381-384, 1948.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF Y - CARBAMYL - Y,Y -DIPHENYLPROPYL - TRIMETHYLAMMONIUM HALIDES, Y - CARBAMYL - Y,Y -DIPHENYLPROPYL - DIMETHYLETHYLAMMONIUM HALIDES,Y-CARBAMYL-Y,Y-DIPHENYLPROPYLMETHYLDIETHYLAMMONIUM HALIDES,Y-CARBAMYL-Y,Y-DIPHENYLPROPYL-TRIETHYLAMMONIUM HALIDES ANDY-CARBAMYL-Y,YDIPHENYLPROPYL-METHYLDIISOPROPYLAMMONIUM HALIDES, SAIDHALIDES BEING SELECTED FROM THE GROUP CONSISTING OF CHLORIDE, BROMIDEAND IODIDE.